The main objective of this research is to elucidate biochemical aspects of the pathogenesis of brain defects due to metabolic aberrations during gestation or early postnatal differentiation. Our rat models (produced by treatment with phenylalanine plus Alpha-methylphenylalanine) for PKU and for offspring of PKU mothers constitute the basic experimental systems. The plans are to elucidate mechanisms which regulate the cerebral concentrations of dopamine and norepinephrine, and to demonstrate the causal relationship of abnormal catecholamine metabolism during development to the permanent alterations in biochemical and behavioral parameters. Among the specific hypotheses to be tested is that a) subnormal dopamine levels interfere with the normal development of nigrostriatal functions, and that b) the resulting deviation from the optimal degree of cerebral lateralization underlies the learning deficits that rats (hyperphenylalaninemic during infancy) exhibit in maze paradigms. The age-dependence of the vulnerability of the brain will be studied by limiting the duration of the experimental hyperphenylalaninemia to specific pre- and postnatal periods. Related to this is the plan to answer the specific question of why hyperphenylalaninemia in early infancy had a more pronounced impact on the growth and on some functional attributes of the female rat brain.